..Moreover, the locked functions reduce the noise level in the calculation, owing to the averaging over the NCS elements, and increase the signals as all monomers of the assembly are taken into account at the same time...

Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate

..This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases...

Crystal structures of substrate complexes of malic enzyme and insights into the catalytic mechanism

..HCMV protease therefore represents example of convergent evolution. In addition, large conformational differences relative to the structure of the free enzyme are observed, which may be important for inhibitor binding...

..The cell parameters for crystal form 1 are a = 65.2 A, b = 74.6 A and c = 78.1 A. Those for crystal form 2 are a = 58.3 A, b = 68.3 A and c = 87.9 A. Diffraction data to 2.0 A resolution have been collected on both forms...

Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors

..Finally, structural comparisons revealed the presence of two conserved structural water molecules at the bottom of the S(1) pocket, suggesting a possible new direction for the design of HCMV protease inhibitors...

A new serine-protease fold revealed by the crystal structure of human cytomegalovirus protease

..A dimer of the protease with an extensive interface is found in the crystal structure. This structure information will help in the design and optimization of inhibitors against herpesvirus proteases...

..The rate of ligand release is less than 1000 s(-1) at 0 degrees C and more than 1000 s(-1) at 30 degrees C. Therefore, loop motion and product release are probably concerted and likely to represent a rate limiting step for chemistry...

Structural basis for self-association and receptor recognition of human TRAF2

Y C ParkDepartment of Biochemistry, The Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021, USANature 398:533-8. 1999

..The trimeric structure of the TRAF domain provides an avidity-based explanation for the dependence of TRAF recruitment on the oligomerization of the receptors by their trimeric extracellular ligands...

Structural basis for signal transduction by the Toll/interleukin-1 receptor domains

..Other protein kinase inhibitors may achieve their specificity through a similar mechanism. The structure also reveals a possible second binding site for this inhibitor, with currently unknown function...

Molecular basis for the inhibition of the carboxyltransferase domain of acetyl-coenzyme-A carboxylase by haloxyfop and diclofop

..Two residues that affect herbicide sensitivity are located in this binding site, and mutation of these residues disrupts the structure of the domain. Other residues in the binding site are strictly conserved among the CT domains...

Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase

..xanthus cells. The pleiotrophic effects of wbgB mutations indicate the importance of LPS O-antigen biosynthesis for various cellular functions in M. xanthus...

Crystal structure of human Taspase1, a crucial protease regulating the function of MLL

Javed A KhanDepartment of Biological Sciences, Columbia University, New York, New York 10027, USAStructure 13:1443-52. 2005

..The structure unexpectedly showed the binding of a chloride ion in the active site, and our kinetic studies confirm that chlorides ions are inhibitors of this enzyme at physiologically relevant concentrations...

..Despite the chemical diversity between haloxyfop and tepraloxydim, the compounds do share two binding interactions to the enzyme, which may be important anchoring points for the development of ACC inhibitors...

Crystal structures of human and Staphylococcus aureus pyruvate carboxylase and molecular insights into the carboxyltransfer reaction

..After an extensive search, it was found that 55% glucose can be used as a cryoprotectant while maintaining the diffraction quality of the crystals; most other commonly used cryoprotectants were detrimental to the diffraction quality...

..The mode of dimerization and the relative arrangement of the HAT-N and HAT-C domains are unique to CstF-77. Our data support a role for CstF dimerization in pre-mRNA 3' end processing...

Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1

Yang ShenDepartment of Biological Sciences, Columbia University, New York City, New York 10027, USABiochemistry 47:5767-73. 2008

..Our studies establish a framework for understanding the regulation of lipid biosynthesis by BRCA1 through its inhibition of ACC1 activity, which could be a novel tumor suppressor function of BRCA1...

..The affinity of inhibitors for the CT domain has been assessed using kinetic and fluorescence anisotropy binding studies. The structural information identifies three regions for drug binding in the active site of CT...

A novel NAD-binding protein revealed by the crystal structure of 2,3-diketo-L-gulonate reductase (YiaK)

..Therefore, our studies demonstrate that two different enzymes, an oxidase and a dehydrogenase, may have evolved to catalyze the first step of NAD biosynthesis in prokaryotes. TM1643 establishes a new class of amino acid dehydrogenases...

An extensively associated dimer in the structure of the C713S mutant of the TIR domain of human TLR2

..Moreover, the structure shows that the BB loop can adopt different conformations, which are required for the formation of this dimer. This asymmetric dimer might represent the TLR2:TLRx heterodimer in the function of this receptor...

..5 M Na2SO4), respectively. Detailed kinetic analysis also showed that, in addition to the 260-fold stabilization of the dimer, the anti-chaotropic agents produced a 7-fold enhancement in the catalytic activity of the dimer...

..Functional studies in intact cells demonstrate the requirement of both the PH and the BEACH domains for activity. A prominent groove at the interface between the two domains may be used to recruit their binding partners...

Crystal structure of human DJ-1, a protein associated with early onset Parkinson's disease

..The side chains of Cys-323 and Met-335 at the bottom of this pocket assume dual conformations in the substrate complex, and mutagenesis studies suggest that the Met-335 residue is important for catalysis...

..The structure suggests intimate association between the PH and the BEACH domains, and surface plasmon resonance studies confirm that the two domains of the protein FAN have high affinity for each other, with a K(d) of 120 nM...

..More potent and specific inhibitors could be designed with structure optimization as this strategy is completely general and can be used to design inhibitors against any serine or cysteine protease...

Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents

..Contrary to current knowledge, the structures show that FK866 should compete directly with the nicotinamide substrate. Our structural and biochemical studies provide a starting point for the development of new anticancer agents...

Crystal structures of murine carnitine acetyltransferase in ternary complexes with its substrates

..Excess Mn2+ could replace Lu3+ in the metal binding site and convert the inactive form back into the open form. This reversible process was slow in both directions because of the same but opposite structural change involved...